| 1. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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| 2. |
- Molnar, Anna E. C., et al.
(författare)
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Macular function measured by binocular mfERG and compared with macular structure in healthy children
- 2015
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Ingår i: Documenta Ophthalmologica. - : Springer Science and Business Media LLC. - 0012-4486 .- 1573-2622. ; 131:3, s. 169-176
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Tidskriftsartikel (refereegranskat)abstract
- To create normative data in children from binocular multifocal ERG (mfERG) recordings and compare results with the macular thickness. Forty-nine 5- to 15-year-old healthy, full-term children were examined with Espion Multifocal System, using DTL electrodes. The stimulus matrix consisted of 37 hexagonal elements. Amplitudes, implicit times and response densities (presented in three rings) of the first-order component P1 were analyzed. Measurements of macular thickness were performed with spectral-domain Cirrus OCT. There were no significant differences between right and left eyes regarding mfERG recordings. Median P1 implicit times of Rings 1-3 of the 46 right eyes were 30.0, 30.0 and 30.8 ms and response densities 20.5, 10.9 and 7.6 nV/deg(2), respectively. Implicit time was longer in boys than in girls (p = 0.009, 0.039, 0.005 in Rings 1-3) and was correlated with age (r (s) = 0.417, 0.316, 0.274 in Rings 1-3). Implicit time in Ring 1 correlated significantly with the inner circle of the OCT measurements (p = 0.014). Binocular mfERG with DTL electrodes is a reliable test of the central macular function in children and correlates with macular structure. As previously not shown, there was a significant difference in implicit time between boys and girls.
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| 3. |
- Molnar, Anna E. C., et al.
(författare)
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Reduction of rod and cone function in 6.5-year-old children born extremely preterm
- 2017
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Ingår i: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 135:8, s. 854-861
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To compare retinal function via full-field electroretinographic (ffERG) recordings in 6.5-year-old children born extremely preterm with children born at term. DESIGN, SETTING, AND PARTICIPANTS A subcohort studywas conducted from July 1, 2010, to January 15, 2014, of the national Extremely Preterm Infants in Sweden Study, including preterm children (<27 weeks' gestational age) and children born at term, at 6.5 years of age and living in the Uppsala health care region in Sweden. Full-field electroretinography was performed binocularly, using DTL electrodes and electroretinographic (ERG) protocols with flash strengths of 0.009, 0.17, 3.0, and 12.0 candelas (cd)/s/m2, together with 30-Hz flicker and 3.0 cd/s/m2 single-cone flash. MAIN OUTCOMES AND MEASURES The ffERG recordingswere analyzed, and their associations with gestational age and retinopathy of prematurity were examined. RESULTS Adequate ffERG recordings were obtained from 52 preterm children (19 girls and 33 boys; mean [SD] age at examination, 6.6 [0.1] years) and 45 children born at term (22 girls and 23 boys; mean [SD] age at examination, 6.6 [0.1] years). Lower amplitudes of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 3.0 cd/s/m2: Mean difference, -48.9 μV [95%CI, -80.0 to -17.9 μV]; P=.003; the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2: Mean difference, -55.7 μV [95%CI, -92.5 to -18.8 μV]; P = .004), as well as of the isolated cone response (30-Hz flicker ERG: Mean difference, -12.1 μV [95%CI, -22.5 to -1.6 μV]; P = .03), were found in the preterm group in comparison with the group born at term. The implicit time of the combined rod and cone responses (the a-wave of the dark-adapted ERG protocol of 12.0 cd/s/m2) was longer (mean difference, 1.2 milliseconds [95%CI, 0.3-2.0 milliseconds]; P = .01) in the preterm group, as were the isolated cone responses (30-Hz flicker ERG: Mean difference, 1.2 milliseconds [95%CI, 0.5-1.8 milliseconds]; P < .001), than in the group born at term. No association was found between the ffERG recordings and gestational age or retinopathy of prematurity in the preterm group. CONCLUSIONS AND RELEVANCE Both rod function and cone function were reduced in children born extremely preterm when compared with children born at term. There was no association with retinopathy of prematurity in the preterm group, which suggests that being born extremely preterm may be one of the main reasons for a general retinal dysfunction.
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| 4. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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| 5. |
- Zewinger, Stephen, et al.
(författare)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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| 6. |
- Andersen, Thomas, et al.
(författare)
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C-X-C Ligand 16 Is an Independent Predictor of Cardiovascular Death and Morbidity in Acute Coronary Syndromes
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 39:11, s. 2402-2410
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The chemokine CXCL16 (C-X-C motif ligand 16) is a scavenger receptor for OxLDL (oxidized low-density lipoproteins) and involved in inflammation at sites of atherosclerosis. This study aimed to investigate the association of CXCL16 with clinical outcome in patients with acute coronary syndrome.Approach and Results:Serial measurements of CXCL16 were performed in a subgroup of 5142 patients randomized in the PLATO trial (Platelet Inhibition and Patient Outcome). Associations between CXCL16 and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and the individual components were assessed by multivariable Cox regression analyses. The hazard ratio per 50% increase in admission levels of CXCL16 analyzed as continuous variable was 1.64 (95% CI, 1.44-1.88), P<0.0001. This association remained statistically significant after adjustment for randomized treatment, clinical variables, CRP (C-reactive protein), leukocytes, cystatin C, NT-proBNP (N-terminal pro-brain natriuretic peptide), troponin T, GDF-15 (growth differentiation factor 15), and other biomarkers; hazard ratio 1.23 (1.05-1.45), P=0.0126. The admission level of CXCL16 was independently associated with cardiovascular death (1.50 [1.17-1.92], P=0.0014) but not with ischemic events alone, in fully adjusted analyses. No statistically independent association was found between CXCL16 measured at 1 month, or change in CXCL16 from admission to 1 month, and clinical outcomes.Conclusions:In patients with acute coronary syndrome, admission level of CXCL16 is independently related to adverse clinical outcomes, mainly driven by an association to cardiovascular death. Thus, CXCL16 measurement may enhance risk stratification in patients with this condition.
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| 7. |
- Parker, William A E, et al.
(författare)
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Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes : findings from the PLATelet inhibition and patient Outcomes (PLATO) study
- 2019
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 30:5, s. 579-588
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Tidskriftsartikel (refereegranskat)abstract
- In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y12 inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.
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| 8. |
- Petri, Rebecca, et al.
(författare)
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let-7 regulates radial migration of new-born neurons through positive regulation of autophagy
- 2017
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Ingår i: EMBO Journal. - : EMBO. - 1460-2075 .- 0261-4189. ; 36, s. 1379-1391
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Tidskriftsartikel (refereegranskat)abstract
- During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2 immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family. Knockdown of let-7 in migrating neuroblasts prevented radial migration and led to an immature morphology of newly formed interneurons. This phenotype was accompanied by a decrease in autophagic activity. Overexpression of Beclin-1 or TFEB in new-born neurons lacking let-7 resulted in re-activation of autophagy and restored radial migration. Thus, these results reveal a miRNA-dependent link between autophagy and adult neurogenesis with implications for neurodegenerative diseases where these processes are impaired.
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| 9. |
- Ueland, Thor, et al.
(författare)
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Admission Levels of DKK1 (Dickkopf-1) Are Associated With Future Cardiovascular Death in Patients With Acute Coronary Syndromes
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 39:2, s. 294-302
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Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes.Approach and Results- We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20-1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02-1.10), P=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00-1.09]; P=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04-1.17]; P=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis.Conclusions- In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.
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| 10. |
- Ueland, Thor, et al.
(författare)
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Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes : Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial
- 2018
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Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Background-Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Methods and Results-The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1year of follow-up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21-1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C-reactive protein, troponin T, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and growth differentiation factor-15). The corresponding rates of non-coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36-1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09-1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1month resulted in an HR of 1.09 (95% CI, 0.89-1.33); for major bleeding after 1month, the HR was 1.33 (95% CI, 0.91-1.96). Conclusions-In patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy.
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